EP2335632A2 - Cathéter avec électrode hélicoïdale - Google Patents

Cathéter avec électrode hélicoïdale Download PDF

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Publication number
EP2335632A2
EP2335632A2 EP10252116A EP10252116A EP2335632A2 EP 2335632 A2 EP2335632 A2 EP 2335632A2 EP 10252116 A EP10252116 A EP 10252116A EP 10252116 A EP10252116 A EP 10252116A EP 2335632 A2 EP2335632 A2 EP 2335632A2
Authority
EP
European Patent Office
Prior art keywords
perforations
distal portion
helical electrode
insertion tube
lumen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP10252116A
Other languages
German (de)
English (en)
Other versions
EP2335632A3 (fr
EP2335632B1 (fr
Inventor
Assaf Govari
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biosense Webster Israel Ltd
Original Assignee
Biosense Webster Israel Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biosense Webster Israel Ltd filed Critical Biosense Webster Israel Ltd
Priority to EP12157864A priority Critical patent/EP2460487A1/fr
Publication of EP2335632A2 publication Critical patent/EP2335632A2/fr
Publication of EP2335632A3 publication Critical patent/EP2335632A3/fr
Application granted granted Critical
Publication of EP2335632B1 publication Critical patent/EP2335632B1/fr
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A61B18/14—Probes or electrodes therefor
    • A61B18/1492—Probes or electrodes therefor having a flexible, catheter-like structure, e.g. for heart ablation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/1815—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using microwaves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B17/32—Surgical cutting instruments
    • A61B17/320068—Surgical cutting instruments using mechanical vibrations, e.g. ultrasonic
    • A61B2017/320069—Surgical cutting instruments using mechanical vibrations, e.g. ultrasonic for ablating tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00005—Cooling or heating of the probe or tissue immediately surrounding the probe
    • A61B2018/00011—Cooling or heating of the probe or tissue immediately surrounding the probe with fluids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A61B18/14—Probes or electrodes therefor
    • A61B2018/1405—Electrodes having a specific shape
    • A61B2018/1407—Loop
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A61B18/14—Probes or electrodes therefor
    • A61B2018/1405—Electrodes having a specific shape
    • A61B2018/1435—Spiral
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/1815—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using microwaves
    • A61B2018/1861—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using microwaves with an instrument inserted into a body lumen or cavity, e.g. a catheter
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2218/00—Details of surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2218/001—Details of surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body having means for irrigation and/or aspiration of substances to and/or from the surgical site
    • A61B2218/002—Irrigation

Definitions

  • the present invention relates generally to medical devices, and specifically to cooling of tissue contacted by an invasive probe within the body.
  • energy is imparted to body tissue locally, in a concentrated dose, and it is desirable to cool the treatment area in order to reduce collateral tissue damage.
  • cardiac ablation therapy is used to treat arrhythmias by heating tissue with radio-frequency (RF) electrical energy to create non-conducting lesions in the myocardium. It has been found that cooling the area of the ablation site reduces tissue charring and thrombus formation.
  • Biosense Webster Inc. (Diamond Bar, California) offers the ThermoCool® irrigated- tip catheter as part of its integrated ablation system.
  • the metal catheter tip which is energized with RF current to ablate the tissue, has a number of peripheral holes, distributed circumferentially around the tip, for irrigation of the treatment site.
  • a pump coupled to the catheter delivers saline solution to the catheter tip, and the solution flows out through the holes during the procedure in order to cool the catheter tip and the tissue.
  • Embodiments of the present invention that are described hereinbelow provide irrigated probes for invasive medical procedures, such as irrigated catheters for use in RF ablation, as well as efficient methods for manufacturing such probes.
  • an invasive probe including an insertion tube containing a lumen for providing an irrigation fluid and including a distal portion having a plurality of perforations therethrough providing fluid communication between the lumen and an outer surface of the insertion tube. At least one helical electrode is fitted over the distal portion of the insertion tube.
  • the probe includes one or more wires that pass through the tube and are electrically coupled to the at least one helical electrode. Additionally or alternatively, the at least one helical electrode covers some of the perforations.
  • the at least one helical electrode includes multiple helical electrodes, which are distributed along the distal portion.
  • the insertion tube is configured for insertion through a blood vessel into a chamber of a heart of a subject, so as to bring the at least one helical electrode into contact with endocardial tissue in the heart.
  • the plurality of the perforations includes at least eight perforations, and possibly at least fifty perforations.
  • the perforations typically have a diameter less than 0.5 mm, and possibly less than 0.2 mm.
  • the perforations may have respective sizes that vary depending on respective longitudinal locations of the perforations.
  • the at least one helical electrode includes a wire coil helically wound about the distal portion of the insertion tube. In another embodiment, the at least one helical electrode includes a tube cut out along a spiral pattern.
  • medical apparatus including a probe, for insertion into a body of a subject.
  • the probe includes an insertion tube containing a lumen and including a distal portion having a plurality of perforations therethrough providing fluid communication between the lumen and an outer surface of the insertion tube, with at least one helical electrode fitted over the distal portion of the insertion tube and configured to contact tissue in the body.
  • An energy generator is coupled to the probe so as to supply electrical energy to the at least one helical electrode.
  • An irrigation pump is coupled to the lumen so as to supply an irrigation fluid via the lumen and the perforations to the tissue.
  • the energy generator is coupled to supply electrical energy to the at least one helical electrode in order to ablate the tissue.
  • the probe may be configured for insertion through a blood vessel into a heart of the subject for ablation of myocardial tissue in the heart.
  • a method for treatment including inserting a probe into a body of a subject.
  • the probe includes an insertion tube containing a lumen and including a distal portion having a plurality of perforations therethrough providing fluid communication between the lumen and an outer surface of the insertion tube, with at least one helical electrode fitted over the distal portion of the insertion tube.
  • the at least one helical electrode is brought into contact with tissue in the body. Electrical energy is applied through the at least one helical electrode to the tissue, and an irrigation fluid is supplied via the lumen and the perforations to the tissue.
  • inserting the probe comprises passing the probe through a blood vessel into a heart of the subject.
  • Applying the electrical energy typically then comprises ablating myocardial tissue in the heart.
  • the fluid is supplied in order to cool the distal portion and the tissue.
  • a method for producing a medical device including creating a plurality of perforations through an outer surface of a distal portion of an insertion tube containing a lumen so as to provide fluid communication between the lumen and an outer surface of the insertion tube.
  • At least one helical electrode including a conductive material, is slid over the distal portion of the insertion tube. The at least one helical electrode is then affixed to the outer surface of the distal portion of the insertion tube.
  • irrigating the area of the ablation site reduces tissue charring, thrombus formation, and adhesion between the ablation electrode and the tissue.
  • Methods and devices for irrigation to date have required that the electrode itself be perforated so that irrigation fluid can pass out of the catheter through the perforations into the treatment area.
  • a perforated electrode of this type and methods for producing the perforations are described, for example, in U.S. Patent Application 12/173,150, filed July 15, 2008 , which is assigned to the assignee of the present patent application and whose disclosure is incorporated herein by reference. Creating the perforations is time-consuming and costly, however, and may weaken the electrode structure.
  • Embodiments of the present invention that are described hereinbelow provide a simple, inexpensive method for producing ring electrodes with irrigation.
  • An invasive probe such as a catheter, is produced with multiple perforations through its outer wall in the area in which a ring electrode is to be placed. The perforations communicate with a lumen inside the probe, which conveys irrigation fluid to the perforations.
  • a conductive coil electrode typically having the form and resilience of a helical spring, is fitted over and fixed to the probe at the desired electrode location. This coil electrode is connected to one or more wires running through the probe, which may be used, for example, to provide RF electrical energy to the coil for ablation therapy.
  • the placement of the coil electrode will typically cover some of the perforations in the wall of the probe, other perforations, in the gaps between the turns of the coil, remain uncovered. During operation, these open perforations provide irrigation throughout the treatment area.
  • the design described above and shown in the figures that follow is easy and inexpensive to manufacture. It provides the benefits achieved by a perforated, irrigated electrode, while avoiding the difficulty and costs of actually creating the perforations in the electrode.
  • This sort of electrode structure can be used in creating multiple ring electrodes along the length of a catheter or other structure, such as lasso.
  • Fig. 1 is a schematic, pictorial illustration of a system 20 for cardiac ablation therapy, in accordance with an embodiment of the present invention.
  • An operator 26 inserts a catheter 28 through a blood vessel into a chamber of a heart 24 of a subject 22, and manipulates the catheter so that a distal portion 32 of the catheter contacts the endocardium in an area that is to be treated.
  • the distal portion of the catheter is perforated to enable irrigation of the treatment area, as shown and described hereinbelow.
  • system 20 resembles systems for cardiac ablation treatment that are known in the art, such as the above-mentioned Biosense Webster system, and the components of such systems may be adapted for use in system 20.
  • RF energy generator 44 in a control console 42 to supply RF energy via a cable 38 to the electrode.
  • an irrigation pump 48 supplies a cooling fluid, such as saline solution, via a tube 40 and a lumen in catheter 28 to the distal portion. Operation of the RF energy generator and the irrigation pump may be coordinated in order to give the appropriate volume of irrigation during ablation, so as to cool the electrode and the tissue without overloading the heart with irrigation fluid.
  • a temperature sensor (not shown in the figures) in distal portion 32 may provide feedback to console 42 for use in controlling the RF energy dosage and/or irrigation volume.
  • Fig. 2 is a schematic side view of a portion of an insertion tube 50 of catheter 28, in accordance with an embodiment of the present invention.
  • the figure shows the distal portion of the insertion tube at a stage of manufacturing before assembly of an electrode onto distal portion 32.
  • Tube 50 typically comprises a suitable biocompatible plastic, such as polyurethane, which is typically about 2.3 mm in diameter, with a wall thickness of about 0.15 mm. These dimensions, however, are given solely by way of illustration, and larger or smaller dimensions may be used depending on application requirements.
  • the outer surface of the distal portion of tube 50 is penetrated by multiple perforations 52, which are distributed over the surface of the distal tip both longitudinally (i.e., along the direction parallel to the longitudinal axis of catheter 28) and circumferentially (along circumferences around the axis).
  • the perforations may be formed in tube 50 by any suitable method known in the art, such as pre-molding of the perforations at the time of fabrication of the tube, or punching or drilling (by laser or mechanical means) the perforations into the tube after extrusion.
  • Distal portion 32 contains an interior reservoir 56, which is fed with irrigation fluid by a lumen 58 inside tube 50.
  • Perforations 52 extend between reservoir 56 and the outer surface of tube 50.
  • reservoir 56 has an inner surface 54, which may be formed, for example, by a fitting a tube of smaller diameter inside tube 50.
  • the reservoir may occupy the entire interior space at the distal tip of tube 50, which may then be closed off by a plug (not shown) proximal to the distal tip, through which lumen 58 feeds.
  • Alternative reservoir configurations will be apparent to those skilled in the art and are considered to be within the scope of the present invention.
  • tube 50 has at least eight perforations, which are less than 0.5 mm in diameter, in order to distribute the irrigation over the area of distal portion 32 both longitudinally and circumferentially without overloading the heart with the cooling fluid.
  • the inventors have found it advantageous, however, to have at least fifty perforations in the distal portion, with diameters no greater than 0.2 mm, and possibly as small as about 0.1 mm.
  • the sizes of the perforations may optionally be varied over the length of the distal tip to compensate for pressure variation and ensure equal flow over the entire length.
  • the perforations at and near the most distal part of the tip may be made larger than the more proximal perforations, which are nearer to the fluid inlet.
  • Fig. 3 is a schematic side view of a coil electrode 60, in accordance with an embodiment of the present invention.
  • Electrode 60 typically comprises a resilient, biocompatible conductive material, such as gold, platinum or iridium wire, or an alloy of such metals.
  • the coil electrode may comprise a wire, which is wound into a helical coil, as shown in the figure, resembling a coil spring.
  • the coil electrode may be made from a tube, which is cut out along a spiral pattern to create a helical shape, using laser cutting, for example.
  • the coil electrode has an inner diameter equal to or slightly smaller than the outer diameter of tube 50, so that the coil will fit snugly over the tube.
  • FIG. 4 is a side view
  • Fig. 5 is a cross-sectional view taken along the line marked V-V in Fig. 4 .
  • Electrode 60 is slid to the desired location on tube 50, and is then glued or otherwise fastened in place.
  • One or more wires 62 inside tube 50 penetrate through the outer surface of the tube (possibly through one of perforations 52) and are soldered or otherwise bonded to electrode 60. Any suitable technique that is known in the art for electrical coupling to ring electrodes may similarly be used for this purpose.
  • Wires 62 run through to the proximal end of catheter 28, where they connect via cable 38 to RF energy generator 44 ( Fig. 1 ).
  • Electrode 60 when electrode 60 is fastened over tube 50, it covers some of the perforations (marked 52B in Fig. 5 ). A sufficient number of the perforations (marked 52A) remain open, however, to provide adequate irrigation of the area contacted by the electrode.
  • This arrangement is advantageous in that it obviates the need for high positional precision in forming perforations 52 in tube 50 and in placing electrode 60 on the tube.
  • lumen 58 Fig. 2
  • the fluid exits tube 50 through perforations 52A to the surrounding tissue while electrode 60 delivers the RF energy in order to ablate the tissue.
  • Fig. 6 is a schematic side view of a lasso catheter 70 with coil electrodes 76, in accordance with an embodiment of the present invention.
  • the lasso catheter insertion tube is formed to define a shaft 72 with a distal portion 74 having a roughly circular lasso shape.
  • This sort of lasso shape can be used, for example, in ablating myocardial tissue along a circular path around the ostia of the pulmonary veins in treatment of atrial fibrillation.
  • Electrodes 76 are distributed around the circumference of distal portion 74. Each electrode is slid into place, fastened, and connected electrically to wires inside catheter 70 in the manner described above. Distal portion 74 may also have perforations (not shown in this figure) for the purpose of irrigation, as in catheter 28. Multiple coil electrodes may likewise be distributed along the length of catheters of other types, as well as on other sorts of tubular probes.
  • a device with a similar sort of irrigated tip may be used in therapies that involve microwave-based or ultrasonic tissue heating.
  • coil electrodes of the type described above may also be used without irrigation on catheters and tubular probes of other types.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Plasma & Fusion (AREA)
  • Medical Informatics (AREA)
  • Otolaryngology (AREA)
  • Physics & Mathematics (AREA)
  • Cardiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Surgical Instruments (AREA)
  • Endoscopes (AREA)
EP10252116.8A 2009-12-16 2010-12-15 Cathéter avec électrode hélicoïdale Not-in-force EP2335632B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP12157864A EP2460487A1 (fr) 2009-12-16 2010-12-15 Cathéter avec électrode hélicoïdale

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US12/639,096 US8920415B2 (en) 2009-12-16 2009-12-16 Catheter with helical electrode

Related Child Applications (2)

Application Number Title Priority Date Filing Date
EP12157864A Division EP2460487A1 (fr) 2009-12-16 2010-12-15 Cathéter avec électrode hélicoïdale
EP12157864A Division-Into EP2460487A1 (fr) 2009-12-16 2010-12-15 Cathéter avec électrode hélicoïdale

Publications (3)

Publication Number Publication Date
EP2335632A2 true EP2335632A2 (fr) 2011-06-22
EP2335632A3 EP2335632A3 (fr) 2011-10-19
EP2335632B1 EP2335632B1 (fr) 2015-07-15

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Family Applications (2)

Application Number Title Priority Date Filing Date
EP10252116.8A Not-in-force EP2335632B1 (fr) 2009-12-16 2010-12-15 Cathéter avec électrode hélicoïdale
EP12157864A Withdrawn EP2460487A1 (fr) 2009-12-16 2010-12-15 Cathéter avec électrode hélicoïdale

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP12157864A Withdrawn EP2460487A1 (fr) 2009-12-16 2010-12-15 Cathéter avec électrode hélicoïdale

Country Status (7)

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US (2) US8920415B2 (fr)
EP (2) EP2335632B1 (fr)
JP (1) JP5726503B2 (fr)
CN (1) CN102138823B (fr)
AU (1) AU2010241463B2 (fr)
CA (1) CA2723038C (fr)
IL (1) IL209451A (fr)

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EP2550924A1 (fr) * 2011-07-28 2013-01-30 Biosense Webster (Israel), Ltd. Système d'ablation intégré utilisant un cathéter à multiples lumières d'irrigation
GB2550414A (en) * 2016-05-20 2017-11-22 Creo Medical Ltd Antenna structure
WO2021024140A1 (fr) * 2019-08-02 2021-02-11 St. Jude Medical, Cardiology Division, Inc. Pointe flexible de prédiction de lésion
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JP5670572B2 (ja) * 2010-08-31 2015-02-18 クック メディカル テクノロジーズ エルエルシーＣｏｏｋ Ｍｅｄｉｃａｌ Ｔｅｃｈｎｏｌｏｇｉｅｓ Ｌｌｃ 焼灼術用オーバーチューブ
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JP6883986B2 (ja) * 2013-11-18 2021-06-09 コーニンクレッカ フィリップス エヌ ヴェＫｏｎｉｎｋｌｉｊｋｅ Ｐｈｉｌｉｐｓ Ｎ．Ｖ． 治療用エネルギ送達を含む治療カテーテル
JP6618523B2 (ja) 2014-04-01 2019-12-18 イノベーションズ イン メディスン，エルエルシー 冷却材流を減少させた温度応答性の灌注式アブレーション電極と関連するその製造方法と使用方法
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EP3193763A4 (fr) * 2014-09-15 2018-05-02 Cathrx Ltd Cathéter d'ablation irrigué et procédé correspondant
US10145646B2 (en) 2014-11-13 2018-12-04 Scott Archery Llc Archery bowstring release enabling sensitivity adjustment
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US9220433B2 (en) 2011-06-30 2015-12-29 Biosense Webster (Israel), Ltd. Catheter with variable arcuate distal section

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EP2550924A1 (fr) * 2011-07-28 2013-01-30 Biosense Webster (Israel), Ltd. Système d'ablation intégré utilisant un cathéter à multiples lumières d'irrigation
EP3001969A1 (fr) * 2011-07-28 2016-04-06 Biosense Webster (Israel), Ltd. Systeme d'ablation integre utilisant un catheter a multiples lumieres d'irrigation
US10743932B2 (en) 2011-07-28 2020-08-18 Biosense Webster (Israel) Ltd. Integrated ablation system using catheter with multiple irrigation lumens
US11135006B2 (en) 2016-05-17 2021-10-05 Creo Medical Limited Electrosurgical cutting tool
GB2550414A (en) * 2016-05-20 2017-11-22 Creo Medical Ltd Antenna structure
US11799206B2 (en) 2016-05-20 2023-10-24 Creo Medical Limited Helical antenna structure
WO2021024140A1 (fr) * 2019-08-02 2021-02-11 St. Jude Medical, Cardiology Division, Inc. Pointe flexible de prédiction de lésion

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US20110144639A1 (en) 2011-06-16
US9131981B2 (en) 2015-09-15
US20130150847A1 (en) 2013-06-13
EP2460487A1 (fr) 2012-06-06
CN102138823A (zh) 2011-08-03
CA2723038C (fr) 2019-09-10
EP2335632A3 (fr) 2011-10-19
CN102138823B (zh) 2016-04-20
EP2335632B1 (fr) 2015-07-15
AU2010241463A1 (en) 2011-06-30
JP5726503B2 (ja) 2015-06-03
CA2723038A1 (fr) 2011-06-16
JP2011125707A (ja) 2011-06-30
IL209451A0 (en) 2011-01-31
AU2010241463B2 (en) 2015-07-02
IL209451A (en) 2016-02-29
US8920415B2 (en) 2014-12-30

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